Latent Epstein-Barr (EBV) infection is associated with both Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL), and EBV antigens expressed in these lymphomas are potential targets for immunotherapy. Although clinical studies with EBV-specific cytotoxic T cells (CTLs) have yielded promising results, their antilymphoma activity is limited by several factors. For example, 1) EBV-specific CTL lines generated by standard methods are dominated by T-cell clones not reactive to the subdominant EBV proteins LMP1 and LMP2 expressed in HD and NHL and 2) infused EBV-specific CTLs do not significantly expand in vivo after adoptive transfer. Our central hypothesis is that by overcoming these limitations, we will enhance the antitumor activity of EBV-specific CTLs and improve clinical outcome in lymphoma patients treated with these cells. To demonstrate the feasibility of this strategy, we propose three specific research aims. AIM 1: We will infuse LMP1- and LMP2-specific CTLs into EBV-positive HD or NHL patients to generate the broadest possible CTL response against the malignant cells, and to ensure that suitable CTL epitopes are available, regardless of the patient's HLA type. AIM 2: We have shown that the infusion of monoclonal antibodies targeting the CD45 antigen results in transient lymphodepletion and enhanced EBV- specific CTL expansion. We will build on these findings and test in an animal model the ability of different vaccines to further enhance the proliferation of adoptively transferred CTLs post lymphodepletion. We hypothesize that the expression of IL-15 or the silencing of SOCS1, in combination with LMP1 and LMP2 expression, will enhance the vaccine-induced proliferation and expansion of LMP1- and LMP2-specific CTLs administered to patients. Finally, in AIM 3, we will test in a second Phase I clinical trial the safety and effects of an optimized vaccine on the expansion, persistence and antitumor effector function of pre-existing or adoptively transferred LMP1- and LMP2-specific CTLs in HD or NHL patients with relapsed disease. Lay summary: The body's immune defenses against cancer are usually not effective because the cancer cells, by themselves, do not attract a strong immune response. Some lymphomas contain parts of the Epstein-Barr virus that do stimulate the immune system. We plan to collect T cells, a component of the immune system, from patients' blood samples and train them to recognize the LMP1 and LMP2 segments of the Epstein-Barr virus. After these cells are returned to the patient, they should attack and destroy the tumors cells that contain LMP1 and LMP2.